Only a fraction of smokers and drinkers develop SCCOC, suggesting that genetic susceptibility plays a role in the etiology of SCCOC. Our previous studies have established that host-cell DNA repair capacity and related genetic variations, as measured by polymorphisms, are susceptibility factors for SCCOC. To date, no published studies have investigated apoptotic capacity as a susceptibility factor for SCCOC. There are at least two known apoptotic pathways, intrinsic and extrinsic, that lead to cell death. While the extrinsic pathway of apoptosis is primarily important in the immunological mechanisms of antigen-induced cell death, the intrinsic or mitochondrial pathway of apoptosis is activated in response to unrepaired DNA damage. Therefore, we hypothesize that genetically determined capacity of the intrinsic apoptotic pathway is associated with risk of SCCOC. In this new proposal, we have the following specific aims: Aim 1: To establish a comprehensive database for 600 prospectively accrued (including 300 recruited in the previous SPORE project), newly diagnosed SCCOC cases and 600 hospital-based and genetically unrelated controls (including 300 recruited in an R01-supported project), frequency-matched by age, sex, ethnicity/race and county of residence; Aim 2: To determine differences in phenotypes of the established intrinsic apoptosis capacity between 300 cases and 300 controls. We will test the hypothesis that CPTinduced apoptotic capacity is lower in SCCOC cases than in controls and is modified by known risk factors such as smoking and alcohol use; Aim 3: To determine the associations between variant apoptotic genotypes and risk of SCCOC in the 600 cases and 600 controls that will have genotyping data for the case-control analysis, which will generate new hypotheses for further validation by future larger studies and the INHANCE group; and Aim 4: To study the correlations between apoptotic phenotypes and functional polymorphisms (genetic variants) in 300 cases and 300 controls. We will test the hypothesis that intrinsic apoptotic capacity is correlated with (predicted by) common functional genetic variants of selected apoptotic genes in 300 cases and 300 controls that will have apoptotic phenotype data. This proposed study is highly hypothesis-driven and expands on our previous work and preliminary data from a novel p53-PHB-PIG3 apoptosis mechanism (see Preliminary Data). Our long-term goal is to identify effective biomarkers for risk assessment and at-risk individuals who can be targeted for primary prevention and early detection of SCCOC. Future studies to test the biomarkers developed through this application may be brought forward through the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, a collaboration of research groups leading large molecular epidemiology studies of head & neck cancer that includes the participation of the Project Leader, Dr. Wei, and Co-Leader, Dr. Sturgis.